1. Technical Field of the Invention
The present invention relates to pharmaceutical, in particular, dermatological compositions based on a compound of the avermectin family in the form of a nanoemulsion comprising oily nanocapsules dispersed in an aqueous phase. This invention also relates to a method for the preparation thereof and to its formulation into medicaments useful for the treatment of dermatological conditions/afflictions, in particular of rosacea.
2. Description of Background and/or Related and/or Prior Art
Ivermectin is a mixture of two compounds belonging to the avermectin class, 5-O-demethyl-22,23-dihydroavermectin A1a and 5-O-demethyl-22,23-dihydroavermectin A1b. They are also known under the trademark of 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b. Ivermectin contains at least 80% of 22,23-dihydroavermectin B1a and less than 20% of 22,23-dihydroavermectin B1b. This active agent forms part of the avermectin class, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale, The extra pharmacopoeia, 29th Edition, Pharmaceutical Press, London). Avermectins include in particular ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin.
Ivermectin is more particularly an antihelminthic. It has already been described in humans in the treatment of Onchocerca volvulus onchocerciasis, gastrointestinal strongyloidiasis (anguillulosis) (product Stromectol®), human sarcoptic scabies (Meinking T L et al., N. Engl. J. Med., 1995 Jul. 6; 333(1):26-30 The treatment of scabies with ivermectin) and in the treatment of diagnosed or suspected microfilaremia in subjects suffering from lymphatic filariasis caused by Wuchereria bancrofti. 
Ivermectin exhibits great instability in the presence of water, and it is particularly difficult to obtain stable pharmaceutical compositions containing it. Indeed, this active ingredient has a very low solubility in water (0.005 mg/ml) and is degraded in a hydrophilic medium. This sensitivity to aqueous media can therefore lead to chemical instability of the active agent and/or to crystallization of the active agent initially solubilized, and limits its formulation in cosmetic or dermatological compositions applied by the topical or oral route.
U.S. Pat. No. 4,389,397 describes the efforts carried out to increase the solubility of ivermectin in an aqueous medium, and in particular proposes solubilizing ivermectin in a mixture of surfactant and organic cosolvents.
Moreover, other concepts have been advanced, such as the solubilization of the active ingredient in a fatty phase (see FR0603452) to improve the stability of this active agent.
However, to prevent the degradation of ivermectin in an aqueous formulation for skin application, it appears advantageous to manipulate the structure of the interface from the ivermectin solubilizing medium and the aqueous phase.
CN 1491551 presents formulations of the ivermectin nanocapsule type in suspension in water produced via polymeric emulsions, that is to say, a solvent-free process employing an in situ polymerization of monomer.
Likewise, FR 2,805,761 describes lipid nanocapsules containing phosphatidylcholines in combination with a hydrophilic cosurfactant derived from polyethylene glycol, Solutol HS 15. However, the presence of a cosurfactant is necessary for the production of the nanocapsules. Moreover, the process for preparing such nanocapsules is carried out by phase inversion (PIT process), which results in the use of temperature cycles in this process. Finally, the active agents are solubilized in an oil composed of medium-chain triglycerides of caprylic and capric acids, which is marketed under the trademark Labrafac WL1349 by GATTEFOSSE.